Atherosclerotic renal artery stenosis (ARAS) is a condition where narrowing of the renal artery decreases blood flow to the kidney and leads to development of renal atrophy and hypertension. ARAS is a major cause of renal failure. It is present in over 7% of individuals over 65 years, in up to 45% of patients with coronary artery disease, and in up to 17% of patients with both type II diabetes and hypertension. Optimal management of patients with ARAS is controversial as both revascularization and/or pharmaceutical treatment often fails to improve renal function. Current paradigms point to inflammatory M1 macrophages as the immune mediator in the development of renal injury in ARAS. However, recent studies suggest that CD4+ T cell activation and differentiation into inflammatory Th1 T cells might be the initial events that lead to M1 macrophage recruitment and differentiation in the stenotic kidney. Despite this correlation between T cells and ARAS, the mechanisms by which T cells are recruited, activated, and mediate development of inflammation, renal injury, and atrophy in the stenotic kidney are not well defined. This is the focus of the proposed studies. We hypothesize that the antigen-independent activation and recruitment of Th1 T cells into the stenotic kidney by renal dendritic cells mediates injury by promoting M1 macrophage differentiation. To test this hypothesis, we develop three specific aims. First, we will determine if renal dendritic cells are necessary for CD4+ T cell recruitment after renal artery stenosis in a mouse model. Our hypothesis predicts that renal dendritic cells are necessary for CD4+ T cell recruitment to the stenotic kidney. To test this idea, we will induce renal artery stenosis in a mouse model lacking dendritic cells and determine if lack of dendritic cells reduces CD4+ T cell activation and thereby protects the stenotic kidney from atrophy. Second, we will address whether antigen-mediated T cell activation is necessary for CD4+ T cell participation in kidney damage after renal artery stenosis in a mouse model. We will induce renal artery stenosis in a transgenic mouse containing only T cells that are specific for a non-self- antigen, and determine if lack of self-antigen protects the stenotic kidney from atrophy. Third, we will determine if Th1 T cells mediate the development of renal injury by promoting M1 macrophage differentiation after renal artery stenosis in mice models. To test this idea, we will induce renal artery stenosis in mice with T cells that are unable to differentiate into Th1 cells and in mice with macrophages that are unable to differentiate into M1 macrophages. The proposed studies will identify immune responses that could be targeted for effective treatment. Thus, the results of these studies will lead to a better understanding of the mechanistic role of CD4+ T cells in the pathophysiology of ARAS, and could potentially lead to development of novel therapy for treatment of this disease.